This invention relates to a non metal containing spirogermanium analog, a pharmaceutical composition containing such an analog and a pharmaceutically acceptable carrier or diluent, and a method of treating rheumatoid arthritis in an animal in need thereof which comprises administering an effective amount of such an analog to such animal.
Geschickter et al., U.S. Pat. No. 4,468,393, issued Aug. 28, 1984, claims a method of treating arthritis using various germanium containing spirogermanium analogs including:
N (3-dimethylaminopropyl) 2-aza 8,8 dimethyl-8-germanspiro [4,5]decane; PA0 N (3 dimethylaminopropyl) 2-aza-8,8 diethyl 8-germanspiro [4,5]decane; PA0 N-(3 dimethylaminopropyl) 2 aza 8,8 dipropyl 8-germanspiro [4,5]decane; and PA0 N (3 dimethylaminopropyl) 2 aza 8,8 dibutyl-8-germanspiro [4,5]decane. PA0 N (3 dimethylaminopropyl) 2-aza 8,8 dimethyl 8-germanspiro [4:5]decane; PA0 N (3 dimethylaminopropyl) 2 aza-8,8 diethyl 8-germanspiro [4:5]decane; PA0 N-(3-dimethylaminopropyl) 2 aza 8,8 dipropyl 8-germanspiro [4:5]decane; and PA0 N (3 dimethylaminopropyl) 2 aza 8,8 dibutyl 8-germanspiro [4:5]decane. PA0 N-(3 dimethylaminopropyl) 9 t butyl 3-azaspiro(5:5)undecane. PA0 4,4 dipropylcyclohexanone PA0 4,4 dibutylcyclohexanone PA0 4,4 dipentylcyclohexanone PA0 4,4 bis(2-methylpropyl)cyclohexanone PA0 4-ethyl-4 butylcyclohexanone PA0 4 methyl-4 (1 methylpropyl)cyclohexanone PA0 4 cyclohexylcyclohexanone PA0 4 decylcyclohexanone PA0 4 (1,1 dimethylethyl)cyclohexanone PA0 4 dimethylaminobutylamine PA0 5 dimethylaminopentylamine PA0 6 dimethylaminohexylamine PA0 7 dimethylaminoheptylamine PA0 3 diethylaminopropylamine PA0 3 (1 piperidine)propylamine PA0 6 (1 piperidine)hexylamine PA0 3-(1-pyrrolidine)propylamine PA0 6 (1-pyrrolidine)hexylamine
Tenoso et al., U.S. Pat. No. 4,654,333, issued Mar. 31, 1987, claims a method for treating multiple sclerosis, which comprises administering to a patient suffering from the same a multiple sclerosis treatment effective amount of a spirogermanium selected from the group consisting of:
Rice et al., J. Heterocycl. Chem., 10(5), 731-735 (1973), (Rice I), disclose the synthesis of N (2-dimethyl aminopropyl) 8,8 dimethyl-2-azaspiro [4,5]decane; N-(2 -dimethylaminopropyl)-8,8 diethyl 2 azaspiro [4,5]decane, N-(3 dimethylaminopropyl) 9,9 dimethyl-3 azaspiro [5,5]undecane, and N(3-dimethylaminopropyl) 9,9 diethyl 3-azaspiro [5,5]undecane. Rice I states that biological evaluation of these amines showed significant inhibition of cancer cell growth in human cancer cells grown in tissue culture. There is no disclosure or suggestion in Rice I that such amines have antiarthritic activity.
Rice et al., J. Heterocycl. Chem., 10(5), 737-741 (1973), (Rice II), disclose the synthesis of N-(2-dimethylaminopropyl)-8,8 dimethyl-8-sila-2 azaspiro [4,5]decane and N (3-dimethylaminopropyl) 9,9 dimethyl 9-sila-3-azaspiro [5,5]undecane, and further state that biological evaluation of such compounds indicated cytotoxic action against human cancer cells grown in tissue culture. There is no disclosure or suggestion in Rice II that such compounds have antiarthritic activity.
Rice et al., U.S. Pat. No. 3,256,277, issued June 14, 1966, (Rice III), claim a compound selected from the group consisting of (I) a compound of the formula ##STR1## wherein A is a ring of at least 5 ring atoms, all of the ring atoms being carbon atoms except for R.sup.1 ; R.sup.1 is selected from the group consisting of oxygen and sulfur; X is selected from the group consisting of at least one of hydrogen, lower alkoxy, lower alkyl, lower alkenyl, cyclo lower alkyl and monocarbocyclic aryl; B is a saturated ring of 5-6 ring atoms, the ring atoms in ring B other than the nitrogen atom being carbon atoms; Y is selected from the group consisting of alkylene and alkenylene of up to 6 carbon atoms; n is 0-1; and R is selected from the group consisting of lower alkyl, lower alkenyl, cyclo lower alkyl, cyclo lower alkenyl, lower and di-lower alkyl and alkenyl amino, saturated heterocyclic selected from the group consisting of morpholino, piperidino, pyrrolidino, piperazino, tetrahydrofuryl and their lower alkyl and alkenyl substituted derivatives, monocarbocyclic aryl, naphthyl, pyridyl, quinolyl, furyl and lower alkoxy; (2) the non-toxic acid addition salts (1); and (3) the non toxic quaternary salts of (1).
Rice III states that such compounds are characterized by their pharmacoloqical activity on the nervous and cardiovascular systems. There is no disclosure or suggestion in Rice III that such compounds have antiarthritic activity.
Rice et al., U.S. Pat. No. 3,282,947, issued November 1, 1966, (Rice IV), claim a compound of the formula ##STR2## wherein R and R.sup.1 are each selected from a different one of the group consisting of:
(a) hydrogen PA1 (b) lower alkyl PA1 (c) aralkyl selected from the group consisting of pyridyl, lower alkyl and phenyl lower alkyl, PA1 (d) di-lower alkylamino lower alkylene, or PA1 (e) hydroxy lower alkylene. PA1 X=silicon or germanium PA1 A and A.sup.1 are the same and either ##STR4## n=0 or 1 B=CH.sub.3 when n is one and B is the same as A when n is zero PA1 R.sup.3 =alkylene or alkenylene PA1 y=2-6 when R.sup.3 is alkylene and 3-4 when R.sup.3 is alkenylene PA1 R.sup.4 and R.sup.5 are the same or different lower alkyls having 1-4 carbon atoms, lower alkenyls having 3-4 carbon atoms, or cyclicized together form a heterocyclic group selected from morpholino, pyrrolidino, piperidino and lower alkyl (1-4 carbon atoms) piperazino in which said lower alkyl is attached to a terminal nitrogen atom. Rice VII state that the bisquaternary salts of such compounds exhibit antihypertensive activity and are particularly useful in blocking ganglionic activity in dogs and other animals. There is no disclosure or suggestion in Rice VII that such compounds have anti-arthritic activity. PA1 m is 1 or 2; PA1 R.sub.1 and R.sub.2 are the same or different and are selected from hydrogen or straight chain, branched chain or cyclic alkyl, provided that the total number of carbon atoms contained by R.sub.1 and R.sub.2 when taken together is 4-10; or R.sub.1 and R.sub.2 are joined together to form a cyclic alkyl group containing 3-7 carbon atoms; PA1 provided that when R.sub.1 and R.sub.2 are CH.sub.3 CH.sub.2, R.sub.3 and R.sub.4 are CH.sub.3 and m is 1or 2, n is other than 3; and further provided that when R.sub.1 is H; R.sub.2 is (CH.sub.3).sub.3 C; R.sub.3 and R.sub.4 are CH.sub.3 and m is 1 or 2, n is other than 3; and further provided that when R.sub.2 is H; R.sub.1 is (CH.sub.3).sub.3 C; R.sub.3 and R.sub.4 are CH.sub.3 and m is 2, n is other than 3; PA1 or a pharmaceutically acceptable salt, hydrate or solvate thereof. PA1 m is 1 or 2; PA1 R.sub.1, R.sub.2, R.sub.5, and R.sub.6 are the same or different and are selected from hydrogen or methyl; PA1 m is 1 or 2; PA1 R.sub.1 and R.sub.2 are the same or different and are selected from hydrogen or straight chain, branched chain or cyclic alkyl, provided that the total number of carbon atoms contained by R.sub.1 and R.sub.2 when taken together is 4-10; or R.sub.1 and R.sub.2 are joined together to form a cyclic alkyl group containing 3-7 carbon atoms; PA1 rheumatoid arthritis PA1 systemic lupus erythematosis PA1 multiple sclerosis PA1 acute transplantation/graft rejection PA1 myasthenia gravis PA1 progressive systemic sclerosis PA1 multiple myeloma PA1 atopic dermatitis PA1 hyperimmunoglobin E PA1 hepatitis B antigen negative chronic active hepatitis PA1 Hashimoto's thyroiditis PA1 Familial Mediterranean fever PA1 Grave's disease PA1 autoimmune hemolytic anemia PA1 primary biliary cirrhosis PA1 inflammatory bowel disease PA1 Compound of Formula (I) or Formula (II) 0.5 g PA1 Methyl Hydroxybenzoate 0.01 g PA1 Propyl Hydroxybenzoate 0.04 g PA1 Purified Water B.P. to 100.00 ml (B.P.=British Pharmacopia)
Rice IV states that such compounds are valuable as intermediates and that they also have undefined pharmacoloqical activity. There is no disclosure or suggestion in Rice IV that such amines have antiarthritic activity.
Rice et al., J. Med. Chem., 6. 388-402 (1963), (Rice V), disclose preparation of a large group of N-dialkyl amino alkyl azaspiroalkanes, and state that potent (but undefined) pharmacological activity has been observed throughout the group, and that of particular note are the marked growth inhibitory effects of certain members (e.g , 3 (3 dimethylamino propyl 9 t butyl 3 azaspiro [5,5]undecane) on cancer cells in tissue culture and objective clinical effects in human cancer cells. There is no disclosure or suggestion in Rice V that such compounds have antiarthritic activity.
Rice et al., J. Heterocycl. Chem., 1(3), 125-127 (1964), (Rice VI), disclose synthetic routes to various symmetrical and unsymmetrical 3,9 diazaspiro [5,5]undecanes. There is no disclosure or suggestion in Rice VI that such compounds have any bioloqical activity.
Rice et al., U.S. Pat. No. 3,825,546, issued July 23, 1974, (Rice VII), claim a compound having the structural formula: ##STR3## wherein
R.sup.1 and R.sup.2 are the same or different alkyl groups of 1-4 carbon atoms
Sanwa KK, European Patent Application Publication Number E0,186,505 A2, published July 2, 1986, claim a composition comprising an organogermanium compound represented by the formula ##STR5## wherein n is an integer of 1 or more, R is hydrogen, alkyl, --COOH, --COOR', phenyl, ##STR6## and R' is a lower alkyl group, and a high molecular carrier for pharmaceutical agents. Sanwa KK disclose that such compounds do not have immunity accelerating action but instead have immunity adjusting or regulating action.
DiMartino et al., J. Pharmacol. Exp. Therapeut., 236, 103-110 (1986) report on the ability of spirogermanium to induce suppressor cells.
Badger et al., Immunopharmacol., 10, 201-207 (1985) report on the generation of suppressor cells in normal rats treated with spirogermanium.
The Australian National University, PCT Patent Application Publication Number WO 85/05031, published Nov. 21, 1985, claim a method of modulating or suppressing the immune response of an animal which comprises the administration of an effective amount of at least one amphiphile which is capable of interacting at the surface of a cell to modify the surface properties thereof so as to inhibit or modify recognition of an antigen by the altered cell. Preferably, the amphiphile is a cationic surfactant, such as a double chained quarternary ammonium surfactant.
Gerschickter Fund, British Patent Application Number 929,739, published June 26, 196, disclose azaspirane compounds of the structure ##STR7## wherein A is a mono or bicyclic carbon ring of at least 5 carbon atoms, X is selected from one or more of hydrogen, alkyl and alkoxy, n is 0 or 1, R.sup.1 is an alkylene chain of 2 to 6 carbon atoms, or an alkylene chain if 2 to 6 carbon atoms substituted by a hydroxyl group on a carbon stom at least beta to either nitrogen, and R.sup.2 is dialkyl, each alkyl group of which has 1 to 6 carbon atoms, or an alkylene chain forming, together with the nitrogen atom to which it is attached, a morpholine, piperidine, pyrrolidine, or piperazine ring, or an alkyl-substituted derivative of any of these containing from 1 to 6 carbon atoms in the substituent group, and the non-toxic acid addition salts thereof. The Gerschickter patent also specifically discloses
The Gerschickter patent also discloses that such compounds are useful for their pharmacoloqical activity on the nervous and cardiovascular system.